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1.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443423

RESUMO

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-ß1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.


Assuntos
Cirrose Hepática Experimental/tratamento farmacológico , Melastomataceae/química , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/sangue , Neovascularização Patológica/sangue , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioacetamida , Regulação para Cima/efeitos dos fármacos , Água , Perda de Peso/efeitos dos fármacos
2.
J Clin Med ; 10(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670126

RESUMO

There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1-7) (Ang-(1-7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.

3.
Clin Sci (Lond) ; 134(23): 3137-3158, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33284956

RESUMO

Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin-angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Hepatopatias/enzimologia , Fígado/enzimologia , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2/patogenicidade , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/genética , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Biomarcadores/metabolismo , COVID-19/enzimologia , COVID-19/etiologia , COVID-19/terapia , Terapia Genética , Humanos , Fígado/fisiopatologia , Fígado/virologia , Hepatopatias/terapia , Hepatopatias/virologia , Camundongos
4.
World J Gastroenterol ; 26(40): 6111-6140, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33177789

RESUMO

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.


Assuntos
Varizes Esofágicas e Gástricas , Hipertensão Portal , Hemorragia Gastrointestinal , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Pressão na Veia Porta
5.
Hepatol Commun ; 3(12): 1656-1673, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31832573

RESUMO

There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang-(1-7). In the present study, we investigated long-term effects of ACE2 delivered by an adeno-associated viral vector and short-term effects of Ang-(1-7) peptide in multiple drug-resistant gene 2-knockout (Mdr2-KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3-6 months of age) and advanced (7-9 months of age) disease compared to control vector-injected Mdr2-KO mice. This was accompanied by increased hepatic Ang-(1-7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang-(1-7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline-infused disease controls. The therapeutic effects of both ACE2 therapy and Ang-(1-7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang-(1-7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen-secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang-(1-7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.

6.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614491

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely based on lifestyle modification, which is difficult to achieve in most patients. Progression of simple fatty liver or steatosis to its severe form non-alcoholic steatohepatitis (NASH) and liver fibrosis has been explained by a 'two-hit hypothesis'. Whilst simple steatosis is considered the first hit, its transformation to NASH may be driven by a second hit. Of several factors that constitute the second hit, advanced glycation end products (AGEs), which are formed when reducing-sugars react with proteins or lipids, have been implicated as major candidates that drive steatosis to NASH via the receptor for AGEs (RAGE). Both endogenous and processed food-derived (exogenous) AGEs can activate RAGE, mainly present on Kupffer cells and hepatic stellate cells, thus propagating NAFLD progression. This review focuses on the pathophysiology of NAFLD with special emphasis on the role of food-derived AGEs in NAFLD progression to NASH and liver fibrosis. Moreover, the effect of dietary manipulation to reduce AGE content in food or the therapies targeting AGE/RAGE pathway on disease progression is also discussed.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Progressão da Doença , Alimentos/efeitos adversos , Células Estreladas do Fígado/metabolismo , Humanos , Macrófagos do Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente
7.
Front Physiol ; 10: 1169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607942

RESUMO

Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl4) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro7-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl4 rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.

8.
Invest Ophthalmol Vis Sci ; 60(1): 209-217, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30641549

RESUMO

Purpose: There is a substantial body of evidence indicating that corneal sensory innervation is affected by pathology in a range of diseases. However, there are no published studies that have directly assessed whether the nerve fiber density of the different subpopulations of corneal sensory neurons are differentially affected. The present study explored the possibility that the intraepithelial nerve fiber density of corneal polymodal nociceptors and cold thermoreceptors are differentially affected in mice fed with a high-fat high cholesterol (HFHC; 21% fat, 2% cholesterol) diet and in those that also have diabetes. Methods: The mice were fed the HFHC diet for the duration of the experiment (up to 40 weeks). Mice in the diabetes group had hyperglycaemia induced with streptozotocin after 15 weeks on the HFHC diet. Age-matched control animals were fed a standard diet. All corneal nerve fibers were labeled with a pan neuronal antibody (antiprotein gene product 9.5), and polymodal nociceptors and cold thermoreceptors were labeled with antibodies directed against transient receptor potential cation channel, subfamily V, member 1 and transient receptor potential cation channel subfamily M member 8, respectively. Results: The mice fed a HFHC diet and those that in addition have hyperglycemia have similar reductions in corneal nerve fiber density consistent with small fiber neuropathy. Importantly, both treatments more markedly affected the intraepithelial axons of cold thermoreceptors than those of polymodal nociceptors. Conclusions: The results provide evidence that distinct subpopulations of corneal sensory neurons can be differentially affected by pathology.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica/efeitos adversos , Epitélio Corneano/inervação , Nociceptores/metabolismo , Termorreceptores/metabolismo , Doenças do Nervo Trigêmeo/etiologia , Nervo Trigêmeo/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Hiperglicemia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Terminações Nervosas/fisiologia , Fibras Nervosas/patologia , Estreptozocina , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/metabolismo , Doenças do Nervo Trigêmeo/metabolismo
9.
World J Gastrointest Pathophysiol ; 10(1): 1-10, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30622832

RESUMO

Chronic liver diseases that inevitably lead to hepatic fibrosis, cirrhosis and/or hepatocellular carcinoma have become a major cause of illness and death worldwide. Among them, cholangiopathies or cholestatic liver diseases comprise a large group of conditions in which injury is primarily focused on the biliary system. These include congenital diseases (such as biliary atresia and cystic fibrosis), acquired diseases (such as primary sclerosing cholangitis and primary biliary cirrhosis), and those that arise from secondary damage to the biliary tree from obstruction, cholangitis or ischaemia. These conditions are associated with a specific pattern of chronic liver injury centered on damaged bile ducts that drive the development of peribiliary fibrosis and, ultimately, biliary cirrhosis and liver failure. For most, there is no established medical therapy and, hence, these diseases remain one of the most important indications for liver transplantation. As a result, there is a major need to develop new therapies that can prevent the development of chronic biliary injury and fibrosis. This mini-review briefly discusses the pathophysiology of liver fibrosis and its progression to cirrhosis. We make a special emphasis on biliary fibrosis and current therapeutic options, such as angiotensin converting enzyme-2 (known as ACE2) over-expression in the diseased liver as a novel potential therapy to treat this condition.

10.
Sci Rep ; 8(1): 10175, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29977014

RESUMO

There is no established medical therapy to treat biliary fibrosis resulting from chronic inflammation in the biliary tree. We have recently shown that liver-specific over-expression of angiotensin converting enzyme 2 (ACE2) of the renin angiotensin system (RAS) ameliorated liver fibrosis in mice. Diminazene aceturate (DIZE), a small molecule drug approved by the US Food and Drug Administration, which is used to treat human trypanosomiasis, has been shown to have antifibrotic properties by enhancing ACE2 activity. In this study we sought to determine the therapeutic potential of DIZE in biliary fibrosis using bile duct ligated and multiple drug resistant gene-2 knockout mice. Additionally, human hepatic stellate (LX-2) and mouse Kupffer (KUP5) cell lines were used to delineate intracellular pathways. DIZE treatment, both in vivo and in vitro, markedly inhibited the activation of fibroblastic stellate cells which was associated with a reduced activation of Kupffer cells. Moreover, DIZE-inhibited NOX enzyme assembly and ROS generation, activation of profibrotic transcription factors including p38, Erk1/2 and Smad2/3 proteins and proinflammatory and profibrotic cytokine release. These changes led to a major reduction in biliary fibrosis in both models without affecting liver ACE2 activity. We conclude that DIZE has a potential to treat biliary fibrosis.


Assuntos
Diminazena/análogos & derivados , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Enzima de Conversão de Angiotensina 2 , Animais , Linhagem Celular , Citocinas/metabolismo , Diminazena/farmacologia , Diminazena/uso terapêutico , Células Estreladas do Fígado , Humanos , Macrófagos do Fígado , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Peptidil Dipeptidase A/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
11.
Curr Gene Ther ; 17(1): 4-16, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28292253

RESUMO

INTRODUCTION: The first human adeno-associated virus (AAV) was originally discovered in 1960s as a contaminant of adenovirus stock preparation and thus it had not been of medical interest. Throughout the last three decades AAV has gained popularity to be used in gene therapy, mainly due to its replicative defectiveness and lack of pathogenicity in human. In addition, its ability to mediate stable and long-term expression in both non-dividing and dividing cells with specific tissue tropism makes AAV one of the most promising candidates for therapeutic gene transfer to treat many inherited as well as non-inherited disorders. Moreover, the use of AAV is not only restricted to overexpression of recombinant transgene, but also to over-express short hairpin RNA and microRNA to knockdown the expression of genes in targeted tissues. DISCUSSION AND CONCLUSION: This review is organized into four parts. In the first part of the review, we discuss about the discovery and history of AAV, followed by detailed AAV biology such as virus genome, virus structure and its life cycle. In the second part of the review, the discussion is centred on the molecular mechanisms of AAV and tissue transduction, including receptor recognition and cell binding, endosomal entry, virus uncoating, nuclear entry and genome replication. Advantages and limitations of using AAV as a safe vehicle for gene delivery is also discussed. In the third part of the review, we discuss about the most commonly used AAV serotypes and variants isolated from human and non-human primates, focusing on their diverse tissue tropisms, transduction efficiency, immunological profiles and their applications in animal studies. Final part of the review focuses on the recent progress of in-vivo gene transfer using AAV for inherited and non-inherited diseases in both preclinical and clinical settings with a special emphasis on potential clinical applications of AAV in the field of liver disease.


Assuntos
Dependovirus/genética , Doenças Genéticas Inatas/terapia , Terapia Genética , Vetores Genéticos/uso terapêutico , Doenças Genéticas Inatas/genética , Genoma Viral , Humanos
12.
World J Gastroenterol ; 22(35): 8026-40, 2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27672297

RESUMO

AIM: To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. METHODS: Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. RESULTS: Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION: In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.


Assuntos
Dieta Hiperlipídica , Produtos Finais de Glicação Avançada/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Acético , Animais , Colesterol/administração & dosagem , Progressão da Doença , Fígado Gorduroso/metabolismo , Frutose/administração & dosagem , Inflamação/metabolismo , Macrófagos do Fígado/citologia , Fígado/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
13.
PLoS One ; 10(9): e0138732, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406236

RESUMO

BACKGROUND & AIMS: Although in cirrhosis with portal hypertension levels of the vasoconstrictor angiotensin II are increased, this is accompanied by increased production of angiotensin (Ang)-(1-7), the endogenous ligand of the Mas receptor (MasR), which blunts hepatic fibrosis and decreases hepatic vascular resistance. Therefore, we investigated the effects of the non-peptidic Ang-(1-7) agonist, AVE0991, in experimental cirrhosis. METHODS: Cirrhosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) intoxication. The coloured microsphere technique assessed portal and systemic hemodynamic effects of AVE0991 in vivo. Hepatic expression of eNOS, p-eNOS, iNOS, JAK2, ROCK and p-Moesin were analyzed by western blots. Activities of ACE and ACE2 were investigated fluorometrically. Moreover, fibrosis was assessed in BDL rats receiving AVE0991. RESULTS: In vivo, AVE0991 decreased portal pressure (PP) in both rat models of cirrhosis. Importantly, systemic effects were not observed. The hepatic effects of AVE0991 were based on upregulation of vasodilating pathways involving p-eNOS and iNOS, as well as by downregulation of the vasoconstrictive pathways (ROCK, p-Moesin). Short-term treatment with AVE0991 decreased the activity of ACE2, long-term treatment did not affect hepatic fibrosis in BDL rats. CONCLUSIONS: The non-peptidic agonist of Ang-(1-7), AVE0991, decreases portal pressure without influencing systemic pressure. Thus, although it does not inhibit fibrosis, AVE0991 may represent a promising new therapeutic strategy for lowering portal pressure.


Assuntos
Imidazóis/administração & dosagem , Cirrose Hepática Experimental/fisiopatologia , Pressão na Veia Porta/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Cirrose Hepática Experimental/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Mol Ther ; 23(9): 1434-43, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25997428

RESUMO

Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1-7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1-7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects.


Assuntos
Dependovirus/genética , Terapia Genética , Vetores Genéticos/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Peptidil Dipeptidase A/genética , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Citocinas/metabolismo , Dependovirus/classificação , Modelos Animais de Doenças , Ativação Enzimática , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Células Estreladas do Fígado/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Peroxidação de Lipídeos/genética , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Testes de Função Hepática , Sistema de Sinalização das MAP Quinases , Masculino , Metoxamina/farmacologia , Camundongos , NADPH Oxidases/metabolismo , Neovascularização Patológica/genética , Especificidade de Órgãos/genética , Estresse Oxidativo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
J Hepatol ; 60(4): 832-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24316518

RESUMO

BACKGROUND & AIMS: Advanced glycation end-products (AGEs) levels are high in western diets and contribute to tissue injury via activation of RAGE (receptor for AGEs) and generation of reactive oxygen species (ROS). Here, we determined if high dietary AGE intake worsens progression of non-alcoholic fatty liver disease (NAFLD). METHODS: Male Sprague Dawley rats were fed a methionine choline deficient (MCD) diet for 6 weeks before 6 weeks of a high AGE MCD diet through baking. They were compared with animals on MCD diet or a methionine choline replete (MCR) diet alone for 12 weeks. Hepatic ROS, triglycerides, biochemistry, picro-sirius morphometry, hepatic mRNA expression and immunohistochemistry were determined. Primary hepatic stellate cells (HSCs) from both MCR and MCD animals were exposed to AGEs. ROS, proliferation and mRNA expression were determined. RESULTS: The high AGE MCD diet increased hepatic AGE content and elevated triglycerides, NADPH dependent superoxide production, HNE adducts, steatosis, steatohepatitis (CD43, IL-6, TNF-α) and fibrosis (α-SMA, CTGF, COL1A, picrosirius) compared to MCD alone. In HSCs, AGEs significantly increased ROS production, bromodeoxyuridine proliferation and MCP-1, IL-6, α-SMA, and RAGE expression in HSCs from MCD but not MCR animals. These effects were abrogated by RAGE or NADPH oxidase blockade. CONCLUSIONS: In the MCD model of NAFLD, high dietary AGEs increases hepatic AGE content and exacerbates liver injury, inflammation, and liver fibrosis via oxidative stress and RAGE dependent profibrotic effects of AGEs on activated HSCs. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.


Assuntos
Dieta/efeitos adversos , Produtos Finais de Glicação Avançada/administração & dosagem , Produtos Finais de Glicação Avançada/toxicidade , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Proliferação de Células , Deficiência de Colina/complicações , Progressão da Doença , Expressão Gênica , Produtos Finais de Glicação Avançada/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
16.
Ecotoxicol Environ Saf ; 96: 139-46, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23849467

RESUMO

The present cross-sectional study investigated 12 perfluoroalkyl substances (PFASs) in serum (n=79) and liver (n=66) samples from patients who had undergone liver transplantation for a range of conditions, such as hepatocellular carcinoma (HCC), cirrhosis due to chronic hepatitis C viral infection (HCV), both HCC and HCV, amyloidosis or acute liver failure. PFAS data from patients were compared to those in control serum (n=25) samples from liver donors with no known liver disease and to those in control liver (n=9) tissues collected during liver resection surgery. All samples showed detectable PFOS (serum: 0.621-126ng/mL; liver: 0.375-42.5ng/g wet wt) and PFOA (serum: 0.437-45.5ng/mL; liver: 0.101-2.25ng/g wet wt) concentrations. In general, in paired serum and liver samples, serum had higher PFOS, PFHxS, PFDA, PFNA, and PFOA concentrations than those in explanted livers from patients. These findings also suggest that pathological changes in diseased livers alter the distribution of PFASs between liver and serum. The results from control serum (2007-2008) suggested that PFOS, PFHxS, PFOA, and PFNA concentrations were lower than those previously reported from Australia for 2002-2003, and 2006-2007. The present study demonstrates, for the first time, the detection and comparison of a range of PFASs in the liver of patients with liver cancer and/or liver cirrhosis.


Assuntos
Fluorcarbonetos/análise , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/química , Fígado/química , Austrália , Estudos Transversais , Fluorcarbonetos/sangue , Humanos
17.
Gastroenterology ; 145(4): 874-884.e5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23796456

RESUMO

BACKGROUND & AIMS: Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. METHODS: We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. RESULTS: Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. CONCLUSIONS: In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.


Assuntos
Angiotensina I/farmacologia , Cirrose Hepática Experimental/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasodilatação/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Humanos , Óxido Nítrico/fisiologia , Peptidil Dipeptidase A/fisiologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Resistência Vascular
18.
World J Gastrointest Pathophysiol ; 4(1): 1-11, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23596549

RESUMO

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesenteric and portal blood flow. Non-selective ß-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis. However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients. Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding. This review briefly outlines current therapeutic approaches to the management of portal hypertension, and the evidence supporting the role of the renin angiotensin system (RAS) and the use of RAS blockers in this condition. It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

19.
Am J Physiol Gastrointest Liver Physiol ; 304(1): G99-108, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23086915

RESUMO

Recent studies have shown that, in cirrhosis, portal angiotensin-(1-7) [Ang-(1-7)] levels are increased and hepatic expression of angiotensin converting enzyme 2 (ACE2) and the Mas receptor are upregulated, but the effects of Ang-(1-7) on hepatic hemodynamics in cirrhosis have not been studied. This study investigated the effects of Ang-(1-7) on vasoconstrictor-induced perfusion pressure increases in cirrhotic rat livers. Ang II or the alpha 1 agonist methoxamine (MTX) were injected in the presence or absence of Ang-(1-7), and the perfusion pressure response was recorded. Denudation of vascular endothelial cells with sodium deoxycholate was used to investigate the contribution of endothelium to the effects of Ang-(1-7). Ang-(1-7) alone had no effect on perfusion pressure. However, it reduced the maximal vasoconstriction response and area under the pressure response curve to Ang II and MTX by >50% (P < 0.05). This effect of Ang-(1-7) was not blocked by Mas receptor inhibition with A779 or by Ang II type 1 and type 2 receptor and bradykinin B(2) receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro(7)-Ang-(1-7), a novel Ang-(1-7) receptor antagonist, completely abolished the vasodilatory effects of Ang-(1-7), as did inhibition of endothelial nitric oxide synthase (eNOS) with N(G)-nitro-L-arginine methyl-ester, guanylate cyclase blockade with ODQ and endothelium denudation. The functional inhibition by D-Pro(7)-Ang-(1-7) was accompanied by significant (P < 0.05) inhibition of eNOS phosphorylation. This study shows that Ang-(1-7) significantly inhibits intrahepatic vasoconstriction in response to key mediators of increased vascular and sinusoidal tone in cirrhosis via a receptor population present on the vascular endothelium that is sensitive to D-Pro(7)-Ang-(1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiologia , Circulação Hepática/efeitos dos fármacos , Cirrose Hepática/fisiopatologia , Metoxamina/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/fisiologia , Fragmentos de Peptídeos/farmacologia , Vasoconstritores/antagonistas & inibidores , Animais , Western Blotting , Endotélio Vascular/metabolismo , Hibridização In Situ , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Metoxamina/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos , Receptor B2 da Bradicinina/efeitos dos fármacos , Vasoconstritores/farmacologia
20.
Clin Sci (Lond) ; 123(4): 225-39, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22548407

RESUMO

The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.


Assuntos
Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Síndrome Hepatorrenal/fisiopatologia , Humanos , Hipertensão Portal/fisiopatologia , Fígado/efeitos dos fármacos , Cirrose Hepática/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
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